Multiple myeloma is the second most common hematologic malignancy. Although conventional chemotherapy can put the disease into remission, relapse is inevitable due to the persistence of selfenewing myeloma cells. Allogeneic hematopoietic stem cell transplant can induce durable remission, demonstrating that immunologic therapy in the form of "graft-versus-tumor effect" can eliminate myeloma progenitor cells and prevent relapse. However, mortality and age barriers prevent the general use of this procedure in myeloma. Therefore, novel immunologic therapies such as tumor vaccines are urgently needed. We discovered that CT7 (MAGE-C1) and MAGE-A3, two members of the Melanoma Antigen Gene family of tumor-associated antigens, were detected in the majority of primary myeloma specimens examined and their expression correlated with both advanced stage of disease and elevated plasma cell proliferation, a measure of dysregulated cell cycle control. These data suggest type I MAGE are promising vaccine targets associated with self-renewing myeloma cells. We developed a novel vaccine formulation, Antigen-ISS DNA conjugate, that stimulated protective, antigen-specific immunity against cancer in an animal model. It is our hypothesis that type I MAGE-ISS DNA conjugate will stimulate protective immunity against multiple myeloma in patients whose tumor cells express these antigens. Our investigation will pursue the following specific aims: 1. To investigate type I MAGE expression in self-renewing multiple myeloma cells and their relation to dysregulation of the cell cycle. 2. To examine the cellular immune response against type I MAGE in myeloma patients and in vitro models of priming or boosting this immunity with type I MAGE-ISS DNA conjugate vaccines. Successful vaccine immunotherapy in multiple myeloma will be a major advance in this disease and may serve as a proof of principle for application of this strategy in other types of cancer.